The present disclosure relates generally to small molecule inhibitor compounds for inhibiting Rac1 activity and their use for treating, preventing, or reducing the incidences of malignant and nonmalignant manifestations, e.g., plexiform neurofibromas that occur in subjects suffering from neurofibromatosis type 1 (NF1). More particularly, the present disclosure relates to small molecule inhibitor compounds that selectively inhibit Rac1 by blocking the interaction of Tiam1 guanine exchange factor (GEF) with the surface groove of Rac1 and to methods of administering these compounds to subjects suffering from NF1.
Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common, pandemic human genetic disorder affecting approximately 1 in 3000 persons. NF1 encodes neurofibromin, a GTPase activating protein (GAP) for p21ras (Ras). Individuals with NF1 experience multiple malignant and nonmalignant manifestations, including plexiform neurofibromas, which affect 25-40% of NF1 patients and produce significant lifelong morbidity and mortality. Prior attempts to utilize standard chemotherapeutic approaches for treatment have failed, likely due to slow growth rates of the tumors. Surgery has been the mainstay of therapy, but gross total resections are difficult and recent institutional studies have shown relapse rates near 50%.
Taking both failures of surgery and traditional cytotoxic chemotherapy into account, many have investigated molecular inhibition of the Ras pathway as a treatment for plexiform neurofibromas. Targeting Ras activation directly proved challenging given its complex post-translational modification. Genetic or pharmacologic attenuation of Ras-directed signaling molecules in neurofibromin-deficient tumorigenic cells or in key lineages of the tumor microenvironment inhibited tumorigenesis. Utilizing a genetically-engineered murine model (GEMM) that consistently forms plexiform neurofibromas, small molecular inhibitors of receptor tyrosine kinase targets upstream of Ras signaling, specifically cKit, with imatinib mesylate were tested with relative success in these GEMMs. Additionally, imatinib mesylate was dispensed on a compassionate basis to a critically-ill 3 year old with an occlusive airway plexiform neurofibroma and within 3 months of treatment, the 3 year old had a 70% reduction in tumor volume along with resolution of all symptoms. Unfortunately, when imatinib mesylate was administered in a phase II clinical trial, 36% of patients suffered tumor progression and only 17% of patients had a measurable tumor response.
The RhoGTPase Rac1 was identified as a molecular mediator of pathological gain-in-function phenotypes in neurofibromin-deficient Schwann cells, mast cells, and monocyte-macrophages. Genetic Rac1 ablation in Schwann cells reduced the number of plexiform neurofibromas by 95%, as compared to intercrossed strains having a functionally intact Rac1 locus (FIG. 1). Rac1 disruption similarly mitigated pathological proliferation and migration of Nf1−/− Schwann cells in vitro. These data suggest that Schwann cells, the genetically established tumor cell of origin, depend on hyperactivity within Ras-Rac-directed pathways and may serve as a target for therapy.
Accordingly, there is a need in the art for additional inhibitors of multiple receptor tyrosine kinases and additional targets downstream of Ras-GTP for use as molecular therapies for plexiform neurofibromas. It would be further advantageous if the inhibitors had reduced toxicity and greater pharmacological activity.